Benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives and their use as anti-coagulants

ABSTRACT

This invention is directed to benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

This application is a divisional of and claims the benefit of U.S. Ser.No. 08/920,319 filed Aug. 27, 1997, now U.S. Pat. No. 6,008,234, whichis a continuation-in-part of U.S. Ser. No. 08/713,066 filed Sep. 12,1996, now abandoned, the disclosure of which is incorporated byreference.

FIELD OF THE INVENTION

The present invention is directed to monocyclic N-heterocyclics whichare substituted by cyclic amino acid or cyclic hydroxy acid derivatives,and their pharmaceutically acceptable salts, which inhibit the enzyme,factor Xa, thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class ofenzymes. A one-to-one binding of factors Xa and Va with calcium ions andphospholipid forms the prothrombinase complex which converts prothrombinto thrombin. Thrombin, in turn, converts fibrinogen to fibrin whichpolymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the convergentpoint of the intrinsic (surface activated) and extrinsic (vesselinjury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363;and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulationcascade has been refined further with the discovery of the mode ofaction of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serineprotease inhibitor with three Kunitz-type domains which competes withfactor Va for free facto, Xa. Once formed, the binary complex of factorXa and TFPI becomes a potent inhibitor of the factor Vlla and tissuefactor complex.

Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the “Xa burst” pathway and by the factorIXa-VIIIa complex (TENase) of the “sustained Xa” pathway in thecoagulation cascade. After vessel injury, the “Xa burst” pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the “sustained Xa”pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the “Xa burst”pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

The primary advantage of inhibiting factor Xa over thrombin in order toprevent coagulation is the focal role of factor Xa versus the multiplefunctions of thrombin. Thrombin not only catalyzes the conversion offibrinogen to fibrin, factor VII to VIIIA, factor V to Va, and factor XIto XIa, but also activates platelets, is a monocyte chemotactic factor,and mitogen for lymphocytes and smooth muscle cells. Thrombin activatesprotein C, the in vivo anti-coagulant inactivator of factors Va andVIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidlyinactivated by antithrombin III (ATIII) and heparin cofactor II (HCII)in a reaction which is catalyzed by heparin or otherproteoglycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique “tethered ligand”thrombin receptor (Cell(1991), Vol. 64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

Published data with the proteins antistasin and tick anti-coagulantpeptide (TAP) demonstrate that factor Xa inhibitors are efficaciousanti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp.371-376; and Science (1990), Vol. 248, pp. 593-596).

The active site of factor Xa can be blocked by either a mechanism-basedor a tight binding inhibitor (a tight binding inhibitor differs from amechanism-based inhibitor by the lack of a covalent link between theenzyme and the inhibitor). Two types of mechanism-based inhibitors areknown, reversible and irreversible, which are distinguished by ease ofhydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67,pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). Aseries of guanidino compounds are examples of tight-binding inhibitors(Thrombosis Res. (1980), Vol. 19, pp. 339-349).Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have alsobeen shown to be tight-binding inhibitors of thrombin (Biochem. (1984),Vol. 23, pp. 85-90), as well as a series of arylamidine-containingcompounds, including 3-amidinophenylaryl derivatives (Thrombosis Res.(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones(Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compoundsdemonstrate poor selectivity for factor Xa.

RELATED APPLICATIONS

European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives which are stated to be capable ofshowing a strong anticoagulant effect through reversible inhibition offactor Xa.

The synthesis of α,α′-bis(amidinobenzylidene)cycloalkanones andα,α′-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity.

Accordingly, in one aspect, this invention provides compounds selectedfrom the group consisting of the following formulae:

wherein:

A is —C(R⁸)═or —N═;

Z¹ and Z² are independently —O—, —N(R⁹)—, —S—, —S(O)—, —S(O)₂—, or—OCH₂—;

R¹ and R⁴ are each independently hydrogen, halo, alkyl, nitro, —OR⁹,—C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or —N(H)S(O)₂R¹²;

R² is —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹², —C(NH)N(H)C(O)R⁹,—C(NH)N(H)S(O)₂R¹², or —C(NH)N(H)C(O)N(H)R⁹;

R³ is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹,—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹¹—C(O)N(R⁹)R¹⁰, —CH(OH)C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —R¹¹—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹¹—C(O)OR⁹, —N(R⁹)C(O)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl);

R⁵ and R⁶ are independently hydrogen, halo, alkyl, haloalkyl, nitro,—N(R⁹)R¹⁰, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —C(O)N(R⁹)CH₂C(O)N(R⁹)R¹⁰,—N(R⁹)C(O)N(R⁹)R¹⁰, —N(R⁹)C(O)R¹⁰, or —N(R⁹)S(O)₂R¹²;

R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4),—O—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4), or —N(R¹⁴)R¹⁵;

R⁸ is hydrogen, alkyl or halo;

each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl);

R¹¹ is a straight or branched alkylene chain;

R¹² is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R¹³ is a mono- , bi- or tri-cyclic carbocyclic ring system containingfrom 3 to 15 carbon atoms which may be partially or fully saturated oraromatic, wherein the carbon atoms may be optionally oxidized andwherein the carbocyclic ring system is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; or

R¹³ is a mono- , bi- or tri-cyclic heterocyclic ring system containingfrom 3 to 15 ring members including carbon and 1 to 4 hetero atomsselected from nitrogen, oxygen and sulfur atoms, wherein the carbon,nitrogen and sulfur atoms may be optionally oxidized and wherein theheterocyclic ring system may be partially or fully saturated or aromaticand is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and isoptionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or—C(O)N(R⁹)R¹⁰;

R¹⁴ and R¹⁵, together with the nitrogen atom, form a mono- , bi- ortri-cyclic heterocyclic ring system containing from 3 to 15 ring membersincluding carbon and 1 to 3 additional hetero atoms selected fromnitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen, orsulfur atoms may be optionally oxidized and wherein the heterocyclicring system may be partially or fully saturated or aromatic and issubstituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and isoptionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or—C(O)N(R⁹)R¹⁰; and

R¹⁶ is —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰;

provided that when R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰)_(n)—R¹³ (where n is 0), R¹³can not be phenyl, naphthyl or piperidinyl substituted by —C(O)OR⁹; whenR⁷ is —O(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0), R¹³ can not be phenyl,naphthyl, piperidinyl or pyrrolidinyl substituted by —C(O)OR⁹; and whenR⁷ is —N(R¹⁴)R¹⁵, R¹⁴ and R¹⁵, together with the nitrogen atom, can notbe piperazinyl or piperidinyl substituted by —C(O)OR⁹;

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides compositions useful intreating a human having

a disease-state characterized by thrombotic activity, which compositioncomprises a therapeutically effective amount of a compound of theinvention as described above, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method of treating a humanhaving a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor Xa, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of inhibiting humanfactor Xa in vitro or in vivo by the administration of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Alkyl” refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing nounsaturation and having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is alkylas defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy(iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), andthe like.

“Alkylene” refers to straight or branched chain divalent radicalconsisting solely of carbonyl and hydrogen, containing no unsaturationand having from one to six carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like.

“Aryl” refers to a phenyl or naphthyl radical.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isalkyl as defined above and R_(b) is aryl as defined above, e.g., benzyl.

“Aryloxy” refers to a radical of the formula —OR_(b) where R_(b) is arylas defined above, e.g., phenoxy and naphthoxy.

“Aralkoxy” refers to a radical of the formula —OR_(c) where R_(c) isaralkyl as defined above, e.g., benzyloxy, and the like.

“Amidino” refers to the radical —C(NH)—NH₂.

“Carbocyclic ring system” refers to a stable 3- to 15-membered ringradical consisting solely of carbon and hydrogen atoms. For purposes ofthis invention, the carbocyclic ring system radical may be a monocyclic,bicyclic or tricyclic ring system, which may include fused or bridgedring systems, and the ring system may be partially or fully saturated oraromatic, and the carbon atoms in the ring system may be optionallyoxidized. Examples of such carbocyclic ring system radicals include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, norbornene,adamantyl, bicyclo[2.2.2]octane and the like.

“Dialkylamino” refers to a radical of the formula —NR_(a)R_(a) whereeach R_(a) is independently an alkyl radical as defined above, e.g.,dimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.

“Dialkylaminocarbonyl” refers to a radical of the formula—C(O)NR_(a)R_(a) where each R_(a) is independently an alkyl radical asdefined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl,diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl,and the like.

“Halo” refers to bromo, chloro, iodo or fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkoxy” refers to a radical of the formula —OR_(f) where R_(f) ishaloalkyl as defined above, e.g., trifluoromethoxy, difluoromethoxy,trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy,3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.

“Heterocyclic ring system” refers to a stable 3- to 15-membered ringradical which consists of carbon atoms and from one to four heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Forpurposes of this invention, the heterocyclic ring system radical may bea monocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclic ring system radical may be optionally oxidized; thenitrogen atom may be optionally quatermized; and the ring system may bepartially or fully saturated or aromatic. The heterocyclic ring systemradical may be attached to the main structure at any heteroatom orcarbon atom which results in the creation of a stable structure.Examples of such heterocyclic ring system radicals include, but are notlimited to, aziridinyl, azetidinyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolinyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, triazolyl,indanyl, isoxazolyl, isoxazolidinyl, morpholinyl; thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolinyl,octahydroisoindolinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, decahydroisoquinolinyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,2-azabicyclo[2.2.2]heptyl and oxadiazolyl.

“(1,2)-Imidazolyl” refers to an imidazolyl radical attached at eitherthe 1- or 2-position.

“(1,2)-Imidazolinyl” refers to a 4,5-dihydroimidazolyl radical attachedat either the 1- or the 2-position.

“Monoalkylamino” refers to a radical of the formula —NHR_(a) where R_(a)is an alkyl radical as defined above, e.g., methylamino, ethylamino,propylamino, and the like.

“Monoalkylaminocarbonyl” refers to a radical of the formula —C(O)NHR_(a)where R_(a) is an alkyl radical as defined above, e.g.,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and thelike.

“(1,2)-Tetrahydropyrimidinyl” refers to a tetrahydropyrimidinyl attachedat either the 1- or 2-position.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline and caffeine.

“Therapeutically effective amount” refers to that amount of a compoundof formula (I) which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for disease-statescharacterized by thrombotic activity. The amount of a compound offormula (I) which constitutes a “therapeutically effective amount” willvary depending on the compound, the disease-state and its severity, andthe age of the human to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

“Treating” or “treatment” as used herein cover the treatment of adisease-state in a human, which disease-state is characterized bythrombotic activity, and include:

(i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

(ii) inhibiting the disease-state, i.e., arresting its development; or

(iii) relieving the disease-state, i.e., causing regression of thedisease-state.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure. The compounds of theinvention and their pharmaceutically acceptable salts may thereforeexist as single stereoisomers, racemates, and as mixtures of enantiomersand diastereomers. All such single stereoisomers, racemates and mixturesthereof are intended to be within the scope of this invention.

The nomenclature used herein is a modified form of the I.U.P.A.C. systemwherein the compounds of the invention are named as derivatives ofbenzamidine. For example, a compound of the invention selected fromformula (I) wherein A is —N═; Z¹ and Z² are both —O—; R¹ is hydroxy; R²is —C(NH)NH₂; R³ is 1-methylimidazolin-2-yl; R⁴ is hydrogen; R⁵ and R⁶are both fluoro; R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ where n is 0, R⁹ ishydrogen, and R¹³ is 1-carboxycyclohex-4-yl, i.e.,

is named herein as4-hydroxy-3-[(4-(N-(1-carboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Utility and Administration

A. Utility

The compounds of the invention are inhibitors of factor Xa and thereforeuseful in disease-states characterized by thrombotic activity based onfactor Xa's role in the coagulation cascade (see Background of theInvention above). A primary indication for the compounds is prophylaxisfor long term risk following myocardial infarction. Additionalindications are prophylaxis of deep vein thrombosis (DVT) followingorthopedic surgery or prophylaxis of selected patients following atransient ischemic attack. The compounds of the invention may also beuseful for indications in which coumarin is currently used, such as forDVT or other types of surgical intervention such as coronary arterybypass graft and percutaneous transluminal coronary angioplasty. Thecompounds are also useful for the treatment of thrombotic complicationsassociated with acute promyelocytic leukemia, diabetes, multiplemyelomas, disseminated intravascular coagulation associated with septicshock, purpura fulminanas associated infection, adult respiratorydistress syndrome, unstable angina, and thrombotic complicationsassociated with aortic valve or vascular prosthesis. The compounds arealso useful for prophylaxis for thrombotic diseases, in particular inpatients who have a high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitro andin vivo diagnostic reagents for selectively inhibiting factor Xa withoutinhibiting other components of the coagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of thecompounds of the invention on factor Xa are simple chromogenic assaysinvolving only serine protease, the compound of the invention to betested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for tPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319).

Another bioassay useful in demonstrating the utility of the compounds ofthe invention in inhibiting factor Xa demonstrates the potency of thecompounds against free factor Xa in citrated plasma. For example, theanticoagulant efficacy of the compounds of the invention will be testedusing either the prothrombin time (PT), or activated partialthromboplastin time (aPTT) while selectivity of the compounds is checkedwith the thrombin clotting time (TCT) assay. Correlation of the K_(i) inthe primary enzyme assay with the K_(i) for free factor Xa in citratedplasma will screen against compounds which interact with or areinactivated by other plasma components. Correlation of the K_(i) withthe extension of the PT is a necessary in vitro demonstration thatpotency in the free factor Xa inhibition assay translates into potencyin a clinical coagulation assay. In addition, extension of the PT incitrated plasma can be used to measure duration of action in subsequentpharmacodynamic studies.

For further information on assays to demonstrate the activity of thecompounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol.19, pp. 579-588.

C. General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral., using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharine, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pennsylvania, 1990). The composition to be administered will, in anyevent, contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. Generally, a therapeutically effective daily dose is from about0.14 mg to about 14.3 mg/kg of body weight per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof; preferably,from about 0.7 mg to about 10 mg/kg of body weight per day; and mostpreferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day.For example, for administration to a 70 kg person, the dosage rangewould be from about 10 mg to about 1.0 gram per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof, preferablyfrom about 50 mg to about 700 mg per day, and most preferably from about100 mg to about 500 mg per day.

Preferred Embodiments

Of the compounds of the invention as set forth above in the Summary ofthe Invention, several groups of compounds are preferred.

A preferred group of compounds is that group wherein the compound isselected from formula (I):

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof.

A preferred subgroup of this group is that subgroup of compounds whereinA is —N═; Z¹ and Z² are independently —O—, —S— or —OCH2—; R¹ and R⁴ areeach independently hydrogen, halo, alkyl or —OR⁹; R² is —C(NH)NH₂,—C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is ureido, guanidino, —OR⁹,—C(NH)NH₂, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, (1,2)-tetrahydropyrimidinyl(optionally substituted by alkyl), (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); R⁵ and R⁶ are independently hydrogen, halo, alkyl or haloalkyl;R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4); each R⁹ and R¹⁰is independently hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹² is alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹³ is a mono- , bi- or tri-cyclic carbocyclicring system containing from 3 to 15 carbon atoms which may be partiallyor fully saturated or aromatic, wherein the carbon atoms may beoptionally oxidized and wherein the carbocyclic ring system issubstituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and isoptionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or—C(O)N(R⁹)R¹⁰; or R¹³ is a mono- , bi- or tri-cyclic heterocyclic ringsystem containing from 3 to 15 ring members including carbon and 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur atoms, whereinthe carbon, nitrogen and sulfur atoms may be optionally oxidized andwherein the heterocyclic ring system may be partially or fully saturatedor aromatic and is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy,aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰,—C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

A preferred class of this subgroup is that class of compounds wherein Ais —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or —OR⁹; R² is —C(NH)NH₂,—C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁴ is hydrogen; R⁵and R⁶ are each halo; R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to4); each R⁹ and R₁₀ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic carbocyclic ring system containing from 3 to15 carbon atoms which may be partially or fully saturated or aromatic,wherein the carbon atoms may be optionally oxidized and wherein thecarbocyclic ring system is substituted by —(C(R⁹)(R¹⁰)_(m)—R¹⁶ (where mis 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl,alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy,—N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or—C(O)N(R⁹)R¹⁰.

A preferred subclass of this class is that subclass of compounds whereinA is —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or —OR⁹; R² is—C(NH)NH₂; R³ is (1,2)-tetrahydropyrimidinyl (optionally substituted bymethyl), (1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); R⁴ is hydrogen;R⁵ and R⁶ are each halo; R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is0); each R⁹ and R¹⁰ is independently hydrogen, alkyl or aralkyl; R¹³ isa carbocyclic ring system selected from the group consisting ofcyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane, andadamantyl, and wherein the ring system is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0), and is optionally substituted byhydroxy, —N(R⁹)R¹⁰, 13 C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or—C(O)N(R⁹)R¹⁰.

Preferred compounds of this subclass of compounds are those compoundswherein R¹ is hydrogen, benzyloxy or hydroxy; R³ is1-methylimidazolin-2-yl; and R⁵ and R⁶ are both fluoro.

Particularly preferred compounds of this subclass are selected from thefollowing:

4-hydroxy-3-[(4-(N-(1-carboxycyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dicarboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,1-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(2-carboxynorbornan-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxybicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-dicarboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,1-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(2-carboxynorbornan-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxybicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Of these compounds, the following are the most preferred:

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Another preferred subclass of this class of compounds is the subclasswherein A is —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or —OR⁹; R² is—C(NH)NH₂, —C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁴ is hydrogen; R⁵and R⁶ are each halo; R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to4); each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic heterocyclic ring system containing from 3to 15 ring members including carbon and 1 to 4 hetero atoms selectedfrom nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen andsulfur atoms may be optionally oxidized and wherein the heterocyclicring system may be partially or fully saturated or aromatic and issubstituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and isoptionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or—C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

Another preferred subgroup of the group of compounds is that subgroupwherein A is —N═; Z¹ and Z² are independently —O—, —S—or —OCH₂—; R¹ andR⁴ are each independently hydrogen, halo, alkyl or —OR⁹; R² is—C(NH)NH₂, —C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is ureido,guanidino, —OR⁹, —C(NH)NH₂, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁵ and R⁶ areindependently hydrogen, halo, alkyl or haloalkyl; R⁷ is—O—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4); each R⁹ and R¹⁰ isindependently hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹² is alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹³ is a mono- , bi- or tri-cyclic carbocyclicring system containing from 3 to 15 carbon atoms which may be partiallyor fully saturated or aromatic, wherein the carbon atoms may beoptionally oxidized and wherein the carbocyclic ring system issubstituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and isoptionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy,aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or—C(O)N(R⁹)R¹⁰; or R¹³ is a mono- , bi- or tri-cyclic heterocyclic ringsystem containing from 3 to 15 ring members including carbon and 1 to 4hetero atoms selected from nitrogen, oxygen and sulfur atoms, whereinthe carbon, nitrogen and sulfur atoms may be optionally oxidized andwherein the heterocyclic ring system may be partially or fully saturatedor aromatic and is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy,aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, —N(R⁹)R¹⁰,—C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

A preferred class of this subgroup is that class of compounds wherein Ais —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or —OR⁹; R² is —C(NH)NH₂,—C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁴ is hydrogen; R⁵and R⁶ are each halo; R⁷ is —O—(C(R⁹)(R¹⁰))_(n)—R³ (where n is 0 to 4);each R⁹ and R¹⁰ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic carbocyclic ring system containing from 3 to15 carbon atoms which may be partially or fully saturated or aromatic,wherein the carbon atoms may be optionally oxidized and wherein thecarbocyclic ring system is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where mis 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl,alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy,—N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or—C(O)N(R⁹)R¹⁰.

A preferred subclass of this class is that subclass of compounds whereinA is —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or —OR⁹; R² is—C(NH)NH₂; R³ is (1,2)-tetrahydropyrimidinyl (optionally substituted bymethyl), (1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); R⁴ is hydrogen;R⁵ and R⁶ are each halo; R⁷ is —O—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0);each R⁹ and R¹⁰ is independently hydrogen, alkyl or aralkyl; R¹³ is acarbocyclic ring system selected from the group consisting ofcyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane, andadamantyl, and wherein the ring system is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0), and is optionally substituted byhydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰; and R¹⁶ is —C(O)OR⁹ or—C(O)N(R⁹)R¹⁰.

Preferred compounds of this subclass are those compounds wherein R¹ ishydrogen, benzyloxy or hydroxy; R³ is 1-methylimidazolin-2-yl; and R⁵and R⁶ are both fluoro.

Particularly preferred compounds of this subclass of compounds areselected from the following:

4-hydroxy-3-[(4-(1-carboxycyclopent-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-4-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1,2-dicarboxycyclopent-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-1-hydroxycyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxynorbornan-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonyl-2-hydroxycyclohexa-3,5-dien-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-1-methyl-2-ethenylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-methoxycarbonylfluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-methoxycarbonyl-2-chlorofluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-3,4,5,-trihydroxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcycloprop-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclopent-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[3.2.1]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-2-hydroxycyclobut-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidaxolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonyladamant-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxy-2-hydroxycyclohexa-3,5-dien-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-1-methyl-2-ethenylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-carboxyfluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-carboxy-2-chlorofluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-3,4,5,-trihydroxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycycloprop-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclopent-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[3.2.1]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxybicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-2-hydroxycyclobut-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxybicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(3-carboxyadamant-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Another preferred subgroup of the group of compounds is that subgroupwherein A is —N═; Z¹ and Z² are independently —O—, —S— or —OCH₂—; R¹ andR⁴ are each independently hydrogen, halo, alkyl or —OR⁹; R² is—C(NH)NH₂, —C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹; R³ is ureido,guanidino, —OR⁹, —C(NH)NH₂, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R₅ and R⁶ areindependently hydrogen, halo, alkyl or haloalkyl; R⁷ is —N(R¹⁴)R¹⁵; eachR⁹ and R¹⁰ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁴ andR¹⁵, together with the nitrogen atom, form a mono- , bi- or tri-cyclicheterocyclic ring system containing from 3 to 15 ring members includingcarbon and 1 to 3 additional hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen, or sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is—C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

A preferred class of this subgroup is that class of compounds wherein Ais —N═; Z¹ and Z² are each —O —; R¹ is hydrogen or —OR⁹; R² is—C(NH)NH₂, —C(NH)N(H)S(O)₂R¹² or —C(NH)N(H)C(O)R⁹;

R³ is (1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁴ is hydrogen; R₅and R⁶ are each halo; each R⁹ and R¹⁰ is independently hydrogen, alkyl,aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl); R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁴ andR¹⁵, together with the nitrogen atom, form a heterocyclic ring systemselected from the group consisting of dihydroisoquinolinyl,tetrahydroisoquinolinyl, 2-azabicyclo[2.2.1]heptyl, azetidenyl,thiazolidinyl, pyrrolyl, pyrrolidinyl, and 2-oxopiperazinyl; and R¹⁶ is—C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

A preferred subclass of this class of compounds is that subclass ofcompounds wherein A is —N═; Z¹ and Z² are each —O—; R¹ is hydrogen or—OR⁹; R² is —C(NH)NH₂; R³ is (1,2)-tetrahydropyrimidinyl (optionallysubstituted by methyl), (1,2)-imidazolyl (optionally substituted bymethyl), or (1,2)-imidazolinyl (optionally substituted by methyl); R⁴ ishydrogen; R⁵ and R⁶ are each halo; each R⁹ and R¹⁰ is independentlyhydrogen, alkyl, or aralkyl; and R¹⁶ is —C(O)OR⁹ or —C(O)N(R⁹)R¹⁰.

Preferred compounds of this subclass are those compounds wherein R¹ ishydrogen, benzyloxy or hydroxy; R³ is 1-methylimidazolin-2-yl; and R⁵and R⁶ are both fluoro.

Particularly preferred compounds of this subclass are those compoundsselected from the following:

4-hydroxy-3-[(4-(2-carboxymethyl-3-oxopiperazin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxydihydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(7-carboxy-2-azabicyclo[2.2.1]hept-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxytetrahydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxyazetidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxythiazolidin-3-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxypyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxy-4-hydroxypyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(4-carboxy-5,5-dimethylthiazolidin-3-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Most preferred compounds of this subclass are selected from thefollowing:

4-hydroxy-3-[(4-(2-carboxypyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

Preparation of Compounds of the Invention

As a matter of convenience, the following description of the preparationof the compounds of the invention is directed to the preparation ofcompounds of formula (I) where A is —N═, Z¹ and Z² are both —O—, R² is—C(NH)NH₂ and R⁷ is —N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ where R⁹ is alkyl oraralkyl, n is 0, and R¹³ is cyclopentyl substituted by —C(O)OR⁹. It isunderstood, however, that similar synthetic processes may be used toprepare other compounds of formula (I), (II), (III), (IV), (V), (VI),and (VII). It is also understood that in the following description,combinations of substituents and/or variables (e.g., R³ and R⁴) on thedepicted formulae are permissible only if such combinations result inchemically stable compounds.

A. Preparation of Compounds of Formulae (Ia) and (Ib)

Compounds of formulae (Ia) and (Ib) are compounds of the invention, asdescribed above in the Summary of the Invention and may be prepared asillustrated below in Reaction Scheme 1, where each X is independentlyhalo; R⁹ is alkyl or aralkyl (optionally substituted by halo, alkyl,aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl,or dialkylaminocarbonyl); and R¹, R³, R⁴, R⁵, and R⁶ are as describedabove in the Summary of the Invention:

The amino acids of formula (B) are commercially available, for examplefrom Aldrich Chemical Co., Sigma Chemical Co., or ICN Biomedicals, Inc.or may be prepared according to methods known to those skilled in theart. In addition, other amino and hydroxy acids of the formulaN(H)(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³, HO—(C(R⁹)(R¹⁰))_(n)—R¹³, and HN(R¹⁴)R¹⁵where each R⁹, R¹⁰, R¹³, R¹⁴ and R¹⁵ are defined above in the Summary ofthe Invention, are also commercially available, for example, fromAldrich Chemical Co., Maybridge Co., and Jannsen Co., or may be preparedaccording to methods known to those skilled in the art, and may besimilarly used in the above Reaction Scheme in place of the compound offormula (B) to produce the corresponding compounds invention where R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰)_(n)—R¹³, —O—(C(R⁹)(R¹⁰))_(n)—R¹³, and —N(R¹⁴)R¹⁵. Thecompounds of formula (A), (D), (F) and (H) are commercially available,for example, from Aldrich Chemical Co., or may be prepared according tomethods known to those skilled in the art. In general, the compounds offormula (Ia) and (Ib) are prepared by first treating a compound offormula (A)(with a compound formula (B) in an aprotic solvent, forexample, DMSO, in the presence of a base, for example, triethylamine, at−20° C. to 50° C., preferably at ambient temperature, for about 20 to 40hours. The compound of formula (C) is then isolated from the reactionmixture by standard techniques, such as extraction, filtration and invacuo removal of solvent .

The resulting compound of formula (C) is then treated with a compound offormula (D) under standard alkylation conditions, for example, in anaprotic solvent, preferably, in acetonitrile, in the presence of a base,for example, sodium hydride, at ambient temperature for 1 to 24 hours,preferably for about 2 hours. The compound of formula (E) is thenisolated from the reaction mixture by standard techniques, such asextraction, in vacuo removal of solvent, and flash chromatography.

The resulting compound of formula (E) in an aprotic solvent, forexample, acetonitrile, is treated with an equimolar amount of a compoundof formula (F) in the presence of a base, for example, cesium carbonate,at temperatures between about 20° C. and 120° C., preferably at ambienttemperature, for a period of time sufficient to complete the desiredreaction as monitored by thin layer chromatography (TLC). The compoundof formula (G) is then isolated from the reaction mixture by standardisolation techniques, such as extraction, in vacuo removal of solvent,and flash chromatography.

The compound of formula (G) in an aprotic solvent, for example, DMSO, isthen treated with an equimolar amount of a compound of formula (H) inthe presence of a base, for example, cesium carbonate, at temperaturesbetween about 20° C. and 120° C., preferably at about 35° C., for aperiod of time sufficient to complete the desired reaction, for example,for about 13 hours. The reaction mixture is cooled to ambienttemperature and the compound of formula (J) is then isolated from thereaction mixture through standard isolated techniques, such asextraction, in vacuo removal of solvent, and flash chromatography.

The compound of formula (J) is dissolved in an anhydrous alkanol,preferably ethanol, and then anhydrous mineral acid, preferably HCl, isadded to the solution over a period of time sufficient to incorporatethe acid into the solution while maintaining the reaction temperaturesat about −78° C. After incorporation is complete, the reaction vessel issealed and the reaction mixture is allowed to warm to ambienttemperature and stirred between 12 and 24 hours, preferably for about 16hours, at ambient temperature. The solvent is removed in vacuo and theresulting residue is dissolved in fresh anhydrous alkanol, preferablyethanol, and then treated with anhydrous ammonia (gas) at temperaturesfrom between ambient temperature and 100° C. for about 1 to about 5hours, preferably for about 2 hours. The compound of formula (Ia) isthen isolated from the reaction mixture by standard isolationtechniques, for example, in vacuo removal of solvent and purification byhigh performance liquid chromatography (HPLC).

Alternatively, instead of treating the resulting residue above withanhydrous ammonia (gas), the resulting residue may be treated with acompound of the formula NH₂OR⁹ to afford the corresponding compound offormula (Ia) wherein R² is —C(NH)N(H)OR⁹.

The compound of formula (Ia) is then hydrolyzed under acid conditions,for example, treatment with a strong mineral acid such as HCl, toproduce the compound of formula (Ib). In addition, during this step, anycompounds of formula (Ia) so produced which contain an ester as a R¹,R³, R⁴, R⁵, R⁶, R⁹, R¹⁰, R¹², R¹³, or R¹⁴ and R¹⁵ (together with thenitrogen atom) substituent are hydrolyzed to compounds that contain thecorresponding acid substituent.

In addition, compounds of formula (Ia) may be treated under standardtransesterification conditions with an alcohol of the formula R⁹OH whereR⁹ is aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl) to produce compounds of the invention where R⁹ isoptionally substituted aryl.

Compounds of formula (Ia) wherein R³ is —C(NH)NH₂ or —C(NH)N(H)OR⁹ areproduced from the corresponding cyano compounds in a similar manner asthat described above for compound of formula (J).

In addition, compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵, R⁶, R¹³,or R¹⁴ and R¹⁵ (together with the nitrogen atom) contains a—C(O)N(R⁹)R¹⁰ group or a —C(O)OR⁹ group (where each R⁹ or R¹⁰ isindependently alkyl, optionally substituted aryl or optionallysubstituted aralkyl) may be hydrolyzed under acidic conditions toprepare corresponding compounds of the invention where R¹, R³, R⁴, R⁵,R⁶, R¹³, or R¹⁴ and R¹⁵ (together with the nitrogen atom) contains a—C(O)OH group.

In addition, compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵, R⁶, R¹³,or R¹⁴ and R¹⁵ contains a —C(O)OR⁹ group where R⁹ is hydrogen, alkyl,optionally substituted aryl or optionally substituted aralkyl may beamidated under standard amidation conditions to form the correspondingcompounds of formula (Ia) where R¹, R³, R⁴, R⁵, R⁶, R¹³, or R¹⁴ and R¹⁵(together with the nitrogen atom) contains a —C(O)N(R⁹)R¹⁰ group whereR⁹ and R¹⁰ are independently hydrogen, alkyl, optionally substitutedaryl or optionally substituted aralkyl.

In addition, compounds of formula (Ia) where R¹, R³, R⁴, R⁵, or R⁶contains a nitro group may be reduced under standard conditions toproduce the corresponding compounds of formula (Ia) where R¹, R³, R⁴,R⁵, or R⁶ contains an amino group, which can be treated with theappropriate alkylating agents or acylating agents to afford thecorresponding compounds of formula (Ia) where R¹, R³, R⁴, R⁵, or R⁶contains —N(R⁹)R¹⁰ or —N(R⁹)C(O)R¹⁰ where each R⁹ and R¹⁰ isindependently hydrogen, alkyl, optionally substituted aryl or optionallysubstituted aralkyl.

Compounds of formula (Ia) may be further treated with the appropriateacid halide, preferably acid chloride, or with the appropriate acidanhydride or an equivalent, to yield compounds of the invention whereinR² is —C(NH)N(H)C(O)R⁹ where R⁹ is hydrogen, alkyl, optionallysubstituted aryl or optionally substituted aralkyl. Alternatively,compounds of formula (Ia) may further be treated with carbamoylchlorides or their equivalents to yield compounds of the invention whereR² is —C(NH)N(H)C(O)OR¹² where R¹² is described above in the Summary ofthe Invention.

Alternatively, compounds of formula (Ia) may be further treated withcompounds of the formula R¹²—S(O)₂-imidazole (where R¹² is described inthe Summary of the Invention) in a polar solvent, such as methylenechoride, at ambient temperature to afford compounds of the inventionwhere R² is —C(NH)N(H)S(O)₂R¹².

Alternatively, compounds of formula (Ia) may be further treated with anappropriately N—R⁹-substituted phenylcarbamate in a polar solvent,preferably methylene chloride, at ambient temperature, for about 6 to 24hours, preferably for about 12hours, to afford compounds of theinvention where R² is —C(NH)N(H)C(O)N(H)R⁹.

In addition, if compounds of formula (B) are already substituted on theamino radical by R⁹ subsitutents as described above in the Summary ofthe Invention, such compounds do not require the alkylation process ofStep 2, as described above in the Reaction Scheme 1.

In addition, compounds of formula (B) which contain additional reactivehydroxy or amino groups may be treated with the appropriate oxygen- ornitrogen-protecting group prior to Step 1 and then deprotected asdesired to provide the free hydroxy or amino groups.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 Compounds of Formula (B)

A. A solution of 1-amino-1-cyclopentanecarboxylic acid (2.0 g, 16 mmol)in absolute ethanol (30 mL) was cooled to −78° C. and HCl (g) bubbled infor 10 minutes. The flask was sealed with a septum and stirred atambient temperature. After 22 hours the mixture was concentrated invacuo to afford 3.0 g (100% yield) of1-ethoxycarbonyl-1-aminocyclopentane, hydrochloric acid salt, as a whitesolid: NMR (CDCl₃) 9.0 (br s, 3), 2.4-1.8 (m, 8), 1.4 (t, 3) ppm.

B. In a similar manner, the following esters are made:

1-ethoxycarbonyl-2-aminocyclopentane;

1-ethoxycarbonyl-2-aminocyclohexane;

1-ethoxycarbonyl-3-aminocyclohexane;

1-ethoxycarbonyl-4-aminocyclohexane;

3-ethoxycarbonylmethyl-2-oxopiperazine;

1,1-diethoxycarbonyl-4-aminocyclohexane;

1,3-diethoxycarbonyl-4-aminocyclohexane;

1-ethoxycarbonyl-1,2-dihydroxycyclobutane;

1-ethoxycarbonyl-3-hydroxycyclobutane;

1-ethoxycarbonyl-2-hydroxycyclopentane;

1,2-diethoxycarbonyl-4-hydroxycyclopentane;

1-ethoxycarbonyl-2-hydroxycyclohexane;

1-ethoxycarbonyl-4-hydroxycyclohexane;

3-ethoxycarbonyidihydroisoquinoline;

3-ethoxycarbonyltetrahydroisoquinoline;

6-ethoxycarbonyl-2-azabicyclo[2.2.1]heptane;

7-ethoxycarbonyl-2-azabicyclo[2.2.1]heptane;

2-ethoxycarbonyl-3-aminonorbornane;

3-ethoxycarbonylazetidine;

4-ethoxycarbonylthiazolidine;

2-ethoxycarbonylpyrroline;

2-ethoxycarbonylpyrrolidine;

2-ethoxycarbonyl-4-hydroxypyrrolidine;

4-ethoxycarbonyl-5,5-dimethylthiazolidine;

1-ethoxycarbonyl-1-aminocyclopropane;

2-ethoxycarbonyl-2-aminonorbornane;

1,3-diethoxycarbonyl-1-aminocyclobutane;

4-ethoxycarbonyl-4-aminoquinuclidine;

1-benzyloxycarbonyl-1,2-dihydroxycyclohexa-3,5-diene;

1-benzyloxycarbonyl-1-hydroxycyclohexane;

9-methoxycarbonyl-9-hydroxyfluorene;

9-methoxycarbonyl-2-chlorofluorene;

1-methoxycarbonyl-1,3,4,5-tetrahydroxycyclohexane;

1-methoxycarbonyl-1-hydroxycyclopropane;

1-methoxycarbonyl-1-hydroxycycloheptane;

1-methoxycarbonyl-1-hydroxycyclopentane;

1-methoxycarbonyl-1-hydroxycyclobutane;

1-methoxycarbonyl-3-hydroxybicyclo[3.2.1]octane;

1-methoxycarbonyl-3-hydroxybicyclo[2.2.1]heptane;

1-methoxycarbonyl-4-hydroxybicyclo[2.2.1]heptane;

1-methoxycarbonyl-3-hydroxyadamantane;

1,3-dimethoxycarbonyl-2,2-dimethyl-4-hydroxy-6-oxocyclohex-5-ene;

1-methoxycarbonyl-3-hydroxymethylbicyclo[2.2.2]octane;

1-methoxycarbonyl-4-hydroxybicyclo[2.2.2]octane; and

1-methoxycarbonyl-1-methyl-2-hydroxy-2-ethenylcyclohexyl.

PREPARATION 2 Compounds of Formula (C)

A. A solution of ethyl 1-amino-1-cyclopentanecarboxylate, hydrochloricacid salt (1.0 g, 5.2 mmol), as prepared above, in acetonitrile (50 mL)was cooled to −15° C. and pentafluoropyridine (0.57 mL, 0.87 g, 5.2mmol) and triethylamine (3.6 mL, 2.6 g, 26 mmol) were added. Theresultant mixture was allowed to warm slowly to ambient temperature andstirred. After 3 days, the mixture was poured into 100 mL of 50% brinein water and 100 mL of ethyl acetate. The aqueous layer was separatedand extracted with another 100 mL of ethyl acetate. The combined organicextracts were dried over MgSO₄, filtered, and concentrated in vacuo toafford 1.3 g (82% yield) of4-N-(1-ethoxycarbonylcyclopent-1-yl)amino-2,3,5,6-tetrafluoropyridine, acompound of formula (C), as a crystalline solid: NMR (CDCl₃) 4.8 (br s,1), 4.2 (q, 2), 2.5-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compound of formula (C) was made:

4-N-(2-methoxycarbonylpyrrolidin-1-yl)amino-2,3,5,6-tetrafluoropyridine.

C. In a similar manner, the following compounds of formula (C) are made:

4-N-(2-ethoxycarbonylcyclopent-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(2-ethoxycarbonylcyclohex-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(3-ethoxycarbonylcyclohex-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(4-ethoxycarbonylcyclohex-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(1-ethoxycarbonylcycloprop-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(2-ethoxycarbonylnorbornan-2-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(3-ethoxycarbonylnorbornan-2-yl)amino-2,3,5,6-tetrafluoropyridine;

4-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(3-ethoxycarbonylcyclobut-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonylcyclopent-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(3,4-diethoxycarbonylcyclopent-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonylcyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(4-ethoxycarbonylcyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(4-ethoxycarbonylcyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonyltetrahydroisoquinolin-3-yl)-2,3,5,6-tetrafluoropyridine;

4-(6-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-2,3,5,6-tetrafluoropyridine;

4-(7-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-2,3,5,6-tetrafluoropyridine;

4-(3-ethoxycarbonylazetidin-1-yl)-2,3,5,6-tetrafluoropyridine;

4-(4-ethoxycarbonylthiazolidin-3-yl)-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonylpyrrolin-1-yl)-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonylpyrrolidin-1-yl)-2,3,5,6-tetrafluoropyridine;

4-(2-ethoxycarbonyl-4-benzyloxypyrrolidin-1-yl)-2,3,5,6-tetrafluoropyridine;

4-(4-ethoxycarbonyl-5,5-dimethylthiazolidin-3-yl)-2,3,5,6-tetrafluoropyridine;

4-(2-methoxycarbonyl-2-benzyloxycyclohexa-3,5-dien-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonylcyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonyl-1-methyl-2-ethenylcyclohex-2-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(2-methoxycarbonylcyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(9-methoxycarbonylfluoren-9-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(9-methoxycarbonyl-2-chlorofluoren-9-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonyl-3,4,5,-benzyloxycyclohex-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonylcycloprop-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonylcyclohept-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonylcyclopent-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(3-methoxycarbonylbicyclo[3.2.1]oct-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(4-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(3-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(1-methoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(3-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-2,3,5,6-tetrafluoropyridine;

4-(4-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-2,3,5,6-tetrafluoropyridine;and

4-(3-methoxycarbonyladamant-1-yl)oxy-2,3,5,6-tetrafluoropyridine.

PREPARATION 3 Compounds of Formula (E)

A. To a solution of4-N-(1-ethoxycarbonylcyclopent-1-yl)amino-2,3,5,6-tetrafluoropyridine(1.3 g, 4.2 mmol) in acetonitrile (40 mL) was added sodium hydride (0.8g, 20 mmol, 60% dispersion in mineral oil). After gas evolution ceased,iodomethane (0.32 mL, 0.72 g, 5.1 mmol) was added and the resultantmixture was stirred at ambient temperature for 1 hour. The mixture wasthen poured into 100 mL of 50% brine/water and 100 mL of ethyl acetate.The aqueous layer was separated and extracted with another 100 mL ofethyl acetate. The combined organic extracts were dried over MgSO₄,filtered, and concentrated in vacuo to afford a light orange oil.Purification by flash chromatography on silica gel afforded 0.89 g (65%yield) of4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-2,3,5,6-tetrafluoropyridine,a compound of formula (E), as a clear, colorless liquid: NMR (CDCl₃) 4.2(q, 2), 3.2 (s, 3), 2.3-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compounds of formula (E) are made:

4-(N-methyl-N-(2-ethoxycarbonylcyclopent-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-methyl-N-(2-ethoxycarbonylcyclohex-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-methyl-N-(3-ethoxycarbonylcyclohex-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-methyl-N-(4-ethoxycarbonylcyclohex-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-methyl-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-ethyl-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-ethyl-N-(1-ethoxycarbonylcycloprop-1-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-ethyl-N-(2-ethoxycarbonylnorbornan-2-yl)amino)-2,3,5,6-tetrafluoropyridine;

4-(N-ethyl-N-(3-ethoxycarbonylnorbornan-2-yl)amino)-2,3,5,6-tetrafluoropyridine;and

4-(N-ethyl-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino)-2,3,5,6-tetrafluoropyridine.

PREPARATION 4 Compounds of Formula (G)

A. To a solution of4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-2,3,5,6-tetrafluoropyridine(0.89 g, 2.8 mmol) in acetonitrile (30 mL) was added2-benzyloxy-5-cyanophenol (0.63 g, 2.8 mmol) and cesium carbonate (1.2g, 3.6 mmol). The resultant mixture was stirred at 60° C. for 1 day. Themixture was then cooled to ambient temperature and poured into 100 mL ofwater and 100 mL of ethyl acetate. The aqueous layer was separated andextracted with another 100 mL of ethyl acetate. The combined organicextracts were washed with 1 M aqueous KOH solution (100 mL), brine (100mL), dried over MgSO₄, filtered, and concentrated in vacuo to afford ayellow oil. Purification by flash chromatography on silica gel afforded0.87 g (60% yield) of4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile,a compound of formula (G), as a clear, colorless oil: NMR (CDCl₃)7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (q, 2), 3.1 (s, 3), 2.3-1.6 (m, 8), 1.3(t, 3) ppm.

B. In a similar manner, the following compound of formula (G) was made:

4-benzyloxy-3-[(4-N-(2-methoxycarbonylpyrrolidin-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile.

C. In a similar manner, the following compounds of formula (G) are made:

4-benzyloxy-3-[(4-N-(2-ethoxycarbonylcyclopent-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2-ethoxycarbonylcyclohex-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(3-ethoxycarbonylcyclohex-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(4-ethoxycarbonylcyclohex-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(1-ethoxycarbonylcycloprop-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2-ethoxycarbonyinorbornan-2-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(3-ethoxycarbonylnorbornan-2-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-ethoxycarbonylcyclobut-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylcyclopent-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]bensonitrile;

4-benzyloxy-3-[(4-(3,4-diethoxycarbonylcyclopent-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylcyclohex-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylcyclohex-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylcyclohex-1-yl)oxy-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile

4-benzyloxy-3-[(4-(2-ethoxycarbonyltetrahydroisoquinolin-3-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(6-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(7-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-ethoxycarbonylazetidin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylthiazolidin-3-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylpyrrolin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyl-4-benzyloxypyrrolidin-1-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonyl-5,5-dimethylthiazolidin-3-yl)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(2-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(2-ethoxycarbonylcyclohex-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(3-ethoxycarbonylcyclohex-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(4-ethoxycarbonylcyclohex-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(1-ethoxycarbonylcycloprop-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(2-ethoxycarbonylnorbornan-2-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(3-ethoxycarbonylnorbornan-2-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-methoxycarbonyl-2-benzyloxycyclohexa-3,5-dien-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclohex-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-1-methyl-2-ethenylcyclohex-2-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-methoxycarbonylcyclohex-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(9-methoxycarbonylfluoren-9-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(9-methoxycarbonyl-2-chlorofluoren-9-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-3,4,5,-tribenzyloxycyclohex-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcycloprop-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclohept-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclopent-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[3.2.1]oct-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile;and

4-benzyloxy-3-[(4-(3-methoxycarbonyladamant-1-yl)oxy-6,3,5-trifluoropyridin-2-yl)oxy]benzonitrile.

PREPARATION 5 Compounds of Formula (J)

A. To a solution of4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile(0.87 g, 1.7 mmol) in DMSO (17 mL) was added3-(1-methylimidazolin-2-yl)phenol (0.32 g, 1.8 mmol) and cesiumcarbonate (0.7 g, 2.1 mmol). The resultant mixture was stirred at 35° C.After 4 days, the mixture was cooled to ambient temperature and pouredinto 100 mL of water and 100 mL of ethyl acetate. The aqueous layer wasseparated and extracted with another 100 mL of ethyl acetate. Thecombined organic extracts were washed with 0.5 M aqueous KOH solution(100 mL), brine (100 mL), dried over MgSO₄, filtered, and concentratedin vacuo to afford4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoripyridin-2-yl)oxy]benzonitrile as a solid foam: NMR (CDCl₃) 7.4-6.8 (m, 12),5.0 (s, 2), 4.2 (q, 2), 3.9 (t, 2), 3.5 (t, 2), 3.2 (s, 3), 2.8 (s, 3),2.4-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compound of formula (J) was made:

4-benzyloxy-3-[(4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methylimidazol-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxyoxy]benzonitrile.

C. In a similar manner, the following compounds of formula (J) are made:

4-benzyloxy-3-[(4-N-(2-ethoxycarbonylcyclopent-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2-ethoxycarbonylcyclohex-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(3-ethoxycarbonylcyclohex-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(4-ethoxycarbonylcyclohex-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(1-ethoxycarbonylcycloprop-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(2-ethoxycarbonyinorbornan-2-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(3-ethoxycarbonylnorbornan-2-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-ethoxycarbonylcyclobut-1-yl)oxy-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyleyclopent-1-yl)oxy-6-(3-(1-methylimidazolin-2-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3,4-diethoxycarbonylcyciopent-1-yl)oxy-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methylimidazolin-2-yl)phenoxyl)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methylimidazolin-2-y)phenoxyl)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methylimidazolin-2-yl)phenoxyl)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyltetrahydroisoquinolin-3-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(6-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-6-(3-(1-methylimadozolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(7-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-6-(3-(1-methylimadozolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-ethoxycarbonylazetidin-1-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonylthiazolidin-3-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylpyrrolin-1-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-ethoxycarbonyl-4-benzyloxypyrrolidin-1-yl)-6-(3-(1-methylimidozolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-ethoxycarbonyl-5,5-dimethylthiazolidin-3-yl)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(2-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(2-ethoxycarbonylcyclohex-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(3-ethoxycarbonylcyclohex-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(4-ethoxycarbonylcyclohex-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-methyl-N-(4,4-diethoxycarbonylcyclohex-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(2,4-diethoxycarbonylcyclohex-1-yl)amino)-6-(3-(1-methylimidazolin-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(1-ethoxycarbonylcycloprop-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(2-ethoxycarbonylnorbornan-2-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;4-benzyloxy-3-[(4-(N-ethyl-N-(3-ethoxycarbonylnorbornan-2-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(N-ethyl-N-(1,3-diethoxycarbonylcyclobut-1-yl)amino)-6-(3-(1-methylimidazolin-)2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-methoxycarbonyl-2-benzyloxycyclohexa-3,5-dien-1-yl)oxy-6-(3-(1-methyl)-imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-1-methyl-2-ethenylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(2-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(9-methoxycarbonylfluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(9-methoxycarbonyl-2-chlorofluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-3,4,5,-tribenzyloxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcycloprop-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclohept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonylcyclopent-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[3.2.1]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(1-methoxycarbonyl-2-benzyloxycyclobut-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;

4-benzyloxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile;and

4-benzyloxy-3-[(4-(3-methoxycarbonyladamant-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzonitrile.

EXAMPLE 1 Compounds of Formula (Ia)

A. A solution of4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzonitrile(1.1 g, 1.6 mmol) in absolute ethanol (30 mL) was cooled to −78° C. andHCl(g) was bubbled through the mixture for 15 min. The resultant mixturewas stirred in a sealed vessel at ambient temperature for 22 hours, thenconcentrated of all volatiles in vacuo without heating to afford a solidwhite foam. This foam was dissolved in absolute ethanol (40 mL) andheated to reflux as NH₃(g) was gently bubbled through the mixture. After3 hours the mixture was cooled to ambient temperature and concentratedin vacuo. Purification by HPLC on a C18 Dynamax column with 20-80%acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt as a white solid: NMR (DMSO-d₆/TFA) 10.2 (brs, 1), 9.0 (br s , 2), 8.8 (br s, 2), 7.3-17.6 (m, 6), 7.0 (d, 2),3.9-4.2 (m, 6), 3.2 (s, 3), 3.0 (s, 3) 2.9 (s, 3), 2.1 (m, 4), 1.6-1.8(m, 4), 1.2 (t, 3) ppm.

B. In a similar manner, the following compounds of formula (I) weremade:

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt: NMR (DMSO-d₆) 10.2 (br s, 1), 9.0 (br s , 2),8.8 (br s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 4.8 (m, 1), 3.8-4.2 (m, 8),3.0 (s, 3), 2.9 (s, 3), 2.3 (m, 1), 1.9 (m, 3), 1.2 (t, 3) ppm;

4-hydroxy-3-[4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt: NMR (DMSO-d₆) 10.2 (br s, 1), 9.0 (br s , 2),8.8 (br s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 4.8 (m, 1), 3.8-4.2 (m, 6),3.6 (s, 3), 3.0 (s, 3), 2.9 (s, 3), 2.3 (m, 1), 1.9 (m, 3), ppm.

C. In a similar manner, the following compounds of formula (I) are made:

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dimethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-methoxycarbonylcyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-1,1-diethoxycarbonylcyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(2-ethoxycarbonylnorbornan-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-ethoxycarbonylbicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-diethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-diethoxycarbonylcyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,1-diethoxycarbonylcyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(2-ethoxycarbonylnorbornan-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylbicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclopent-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohex-4-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1,2-dimethoxycarbonylcyclopent-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-1-hydroxycyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylnorbornan-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonylmethyl-3-oxopiperazin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-ethoxycarbonyidihydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(7-ethoxycarbonyl-2-azabicyclo[2.2.1]hept-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-ethoxycarbonyltetrahydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-ethoxycarbonylazetidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-ethoxycarbonylthiazolidin-3-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonyl-4-hydroxypyrrolidin-1-yl)-6-(3-(1-methyl)imadozalin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-ethoxycarbonyl-5,5-dimethylthiazolidin-3-y)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonyl-2-hydroxycyclohexa-3,5-dien-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-1-methyl-2-ethenylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylcyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-methoxycarbonylfluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-methoxycarbonyl-2-chlorofluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonyl-3,4,5,-trihydroxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcycloprop-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclohept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-methoxycarbonylcyclopent-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[3.2.1]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidizalin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;4-hydroxy-3-[(4-(1-methoxycarbonyl-2-hydroxycyclobut-1-yl)oxy-6-(3-(1-methyl)imidazalin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-methoxycarbonylbicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(3-methoxycarbonyladamant-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

EXAMPLE 2

Compounds of Formula (Ib)

A. A solution of4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacet acid salt (0.80 g, 1.2 mmol) in 25 mL of 6 N aqueous HClwas stirred at 60° C. for 1 hour. It was then cooled to ambienttemperature, diluted with acetonitrile and trifluoroacetic acid andpurified by HPLC on a C18 Dynamax column with 20-80% acetonitrile inwater gradient with 0.1% trifluoroacetic acid to afford4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacet acid salt as a white solid: NMR (DMSO-d₆)/TFA) 10.2 (br s,1), 9.0 (br s , 2), 8.8 (br s, 2), 7.3-7.6, (m, 6), 7.0 (d, 2), 4.1 (m,2), 3.9 (m, 2), 3.2 (s, 3), 3.0 (s, 3), 2.9 (s, 3), 2.1 (m, 4), 1.6-1.8n(m, 4) ppm.

B. In a similar manner, the following compound of formula (I) was made:4-hydroxy-3-[(4-(N-(2-carboxypyrrolidin-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine,trifluoroacetic acid salt: NMR (DMSO-d₆) 10.2 (br s, 1), 9.0 (br s , 2),8.8 (br s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 4.7 (m, 1), 3.8-4.1 (m, 6),3.0 (s, 3), 2.3 (m, 1), 1.9 (m, 3) ppm.

C. In a similar manner, the following compounds of formula (I) are made:

4-hydroxy-3-[(4-(N-(1-carboxycyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dicarboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,3-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1,1-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(2-carboxynorbornan-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-(1-carboxybicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-dicarboxycyclopent-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopropyl-1-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-3-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,3-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1,1-dicarboxycyclohex-4-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(2-carboxynorbornan-3-yl)amino)-6-(3-1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(N-methyl-N-(1-carboxybicyclo[2.2.2]oct-2-yl)amino)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclopent-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-4-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1,2-dicarboxycyclopent-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-1-hydroxycyclobut-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxynorbornan-3-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxymethyl-3-oxopiperazin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxydihydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(6-carboxy-2-azabicyclo[2.2.1]hept-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxytetrahydroisoquinolin-2-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-1(4-(3-carboxyazetidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxythiazolidin-3-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxypyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-methoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-ethoxycarbonylpyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxy-4-hydroxypyrrolidin-1-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxy-5,5-dimethylthiazolidin-3-yl)-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxy-2-hydroxycyclohexa-3,5-dien-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-1-methyl-2-ethenylcyclohex-2-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(2-carboxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-carboxyfluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(9-carboxy-2-chlorofluoren-9-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-3,4,5,-trihydroxycyclohex-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycycloprop-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclohept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxycyclopent-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[3.2.1]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxybicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[2.2.2]oct-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(1-carboxy-2-hydroxycyclobut-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(3-carboxybicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;

4-hydroxy-3-[(4-(4-carboxybicyclo[2.2.1]hept-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine;and

4-hydroxy-3-[(4-(3-carboxyadamant-1-yl)oxy-6-(3-(1-methyl)imidazolin-2-yl)phenoxy-3,5-difluoropyridin-2-yl)oxy]benzamidine.

EXAMPLE 3

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(4-(N-methyl-N-(1-ethoxycarbonylcyclopent-1-yl)amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

A. Ingredients % wt./wt. Compound of the invention 20.0% Lactose 79.5%Magnesium stearate  0.5%

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each, one capsule would approximate a totaldaily dosage.

B. Ingredients % wt./wt. Compound of the invention 20.0%  Magnesiumstearate 0.9% Starch 8.6% Lactose 69.6%  PVP (polyvinylpyrrolidine) 0.9%

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

C. Ingredients Compound of the invention 0.1 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

D. Ingredients % wt./wt. Compound of the invention 20.0% Peanut Oil78.0% Span 60  2.0%

The above ingredients are melted, mixed and filled into soft elasticcapsules.

E. Ingredients % wt./wt. Compound of the invention 1.0% Methyl orcarboxymethyl cellulose 2.0% 0.9% saline q.s. 100 mL

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 4

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,4-hydroxy-3-[(4-(N-(2-ethoxycarbonylpyrrolidin-1-yl)-amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 gPolyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% Saline solutionq.s. 100 mL

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2μ membrane filter andpackaged under sterile conditions.

EXAMPLE 5

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(4-(N-(2-ethoxycarbonylpyrrolidin-1-yl)-amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

Ingredients % wt./wt. Compound of the invention  1.0% Polyethyleneglycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 6

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[4-(N-(2-methoxycarbonylpyrrolidin-1-yl)-amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

Ingredients % wt./wt. Micronized compound of the invention  1.0%Micronized lactose 99.0%

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 7

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[4-(N-(2-methoxycarbonylpyrrolidin-1-yl)-amino)-6-(3-(1-methylimidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

Ingredients % wt./wt. Compound of the invention  0.005% Water 89.995%Ethanol 10.000%

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 8

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,4-hydroxy-3-[(4-(N-methyl-N-(1-carboxycyclopent-1-yl)amino)-6-(3-(1-methyl-imidazolin-2-yl)phenoxy)-3,5-difluoropyridin-2-yl)oxy]benzamidine:

Ingredients % wt./wt. Compound of the invention 0.10% Propellant 11/1298.90%  Oleic acid 1.00%

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 9 In Vitro Assay for Factor Xa and Thrombin

This assay demonstrates the activity of the compounds of the inventiontowards factor Xa, thrombin and tissue plasminogen activator. Theactivities were determined as an initial rate of cleavage of the peptidep-nitroanilide by the enzyme. The cleavage product, p-nitroaniline,absorbs at 405 nm with a molar extinction coefficient of 9920 M⁻¹cm⁻¹.

Reagents and Solutions

Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

Assay buffer:

50 mM Tris HCl, 150 mM NaCl, 2.5 mM CaCl₂, and 0.1% polyethylene glycol6000, pH 7.5.

Enzymes (Enzyme Research Lab.):

1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer, storedat −80° C. (working solution (2×): 106 ng/mL or 2 nM in assay buffer,prepare prior to use).

2. Human thrombin stock solution: Stored at −80° C. (working solution(2×): 1200 ng/mL or 40 nM in assay buffer, prepare prior to use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) stocksolution: 1 mglmL, stored at −80° C. (working solution (2×): 1361 ng/mLin assay buffer, prepare prior to use).

Chromogenic substrates (Pharmacia Hepar Inc.):

1. S2222 (FXa assay) stock solution: 6 mM in deionized H₂O, store at 4°C. (working solution (4×): 656μM in assay buffer).

2. S2302 (Thrombin assay) stock solution: 10 mM in deionized H₂O, storedat 4° C. (working solution (4×): 1200 μM in assay buffer).

3. S2288 (tPA assay) stock solution: 10 mM in deionized H₂O, stored at4° C. (working solution (4×): 1484 μM in assay buffer).

Standard inhibitor compound stock solution:

5 mM in DMSO, stored at −20° C.

Test compounds (compounds of the invention) stock solutions:

10 mM in DMSO, stored at −20° C.

Assay Procedure:

Assays were performed in 96-well microtiter plates in a total volume of200 μl. Assay components were in final concentration of 50 mM TrisHCl,150 mM NaCI, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH 7.5, in theabsence or presence of the standard inhibitor or the test compounds andenzyme and substrate at following concentrations: (1) 1 nM factor Xa and164 μM S2222; (2) 20 nM thrombin and 300 μM S2302; and (3) 10 nM tPA and371 μM S2288. Concentrations of the standard inhibitor compound in theassay were from 5 μM to 0.021 μM in 1 to 3 dilution. Concentration ofthe test compounds in the assay typically were from 10 μM to 0.041 μM in1 to 3 dilution. For potent test compounds, the concentrations used inthe factor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or1000 fold (10 nM to 0.041 nM). All substrate concentrations used areequal to their K_(m) values under the present assay conditions. Assayswere performed at ambient temperature.

The first step in the assay was the preparation of 10 mM test compoundstock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4×) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (orMultiprobe 204) in 96 deep well plates as follows:

(a) Prepare a 40 μM working solution by diluting the 10 mM stock 1 to250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

(b) Make another five serial dilutions (1:3) of the 40 μM solution (600μl for each concentration). A total of six diluted test compoundsolutions were used in the assay.

Standard inhibitor compound (5 mM stock) or DMSO (control) went throughthe same dilution steps as those described above for test compounds.

The next step in the assay was to dispense 50 μl of the test compoundworking solutions (4×) (from 40 μM to 0.164 μM) in duplicate tomicrotiter plates with Biomek or MP204. To this was added 100 μL ofenzyme working solution (2×) with Biomek or MP204. The resultingsolutions were incubated at ambient temperature for 10 minutes.

To the solutions was added 50 μL of substrate working solution (4×) withBiomek or MP204.

The enzyme kinetics were measured at 405 nm at 10 seconds intervals forfive minutes in a THERMOmax plate reader at ambient temperature.

Calculation of K_(i) of the Compounds of the Invention

Enzyme rates were calculated as mOD/min based on the first two minutesreadings. The IC₅₀ values were determined by fitting the data to thelog-logit equation (linear) or the Morrison equation (non-linear) withan EXCEL spread-sheet. Ki values were then obtained by dividing the IC₅₀by 2. Routinely, Ki(factor Xa) values less than 3 nM were calculatedfrom the Morrison equation.

Compounds of the invention, when tested in this assay, demonstrated theselective ability to inhibit human factor Xa and human thrombin.

EXAMPLE 10 In vitro assay for Human Prothrombinase

This assay demonstrates the ability of the compounds of the invention toinhibit prothrombinase. Prothrombinase (PTase) catalyzes the activationof prothrombin to yield fragment 1.2 plus thrombin with meizothrombin asthe intermediate. This assay is an end point assay. Activity of theprothrombinase is measured by activity of thrombin (one of the reactionproducts) or by the amount of thrombin formed/time based on a thrombinstandard curve (nM vs mOD/min). For determination of IC₅₀ (PTase) of thecompounds of the invention, PTase activity was expressed by thrombinactivity (mOD/min).

Materials:

Enzymes:

1. Human factor Va (Haematologic Technologies Inc., Cat# HCVA-0110)working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at −20°C.

2. Human factor Xa (Enzyme Res. Lab. cat# HFXa1011) working solution:0.281 mg/mL in assay buffer (without BSA), stored at −80° C.

3. Human prothrombin (FII) (Enzyme Res. Lab., Cat# HP1002) workingsolution: Diluted FII to 4.85 mg/mL in assay buffer (without BSA),stored at −80° C.

Phospholipid (PCPS) vesicles.

PCPS vesicles (80%PC, 20%PS) were prepared by modification of the methodreported by Barenholz et al., Biochemistry (1977), Vol.16, pp.2806-2810. Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032):

10 mg/mL in chloroform, purified from brain, stored −20° C. undernitrogen or argon.

Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat# 850457):

50 mg/mL in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at−20° C. under nitrogen or argon.

Spectrozyme-TH (American Diagnostica Inc., Cat# 238L, 50 μmoles, storedat room temperature) working solution: Dissolved 50 μmoles in 10 mLdeionized H₂O .

BSA (Sigma Chem Co., Cat# A-7888, FractionV, RIA grade).

Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% PEG6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

For one plate assay, prepare the following working solutions:

1 Prothrombinase complex:

(a) 100 μM PCPS (27.5 μl of PCPS stock (4.36 mM) diluted to final 1200μl with assay buffer.

(b) 25 nM Human factor Va: 5.08 μl of Va stock(1 mg/mL) was diluted tofinal 1200 μL with assay buffer.

(c) 5 μM Human factor Xa: Dilute factor Xa stock (0.281 mg/mL)1:1,220,000 with assay buffer. Prepare at least 1200 μL.

Combine equal volumes (1100 μL) of each component in the order of PCPS,Va and Xa.

Let stand at ambient temperature for 5 to 10 minutes and use immediatelyor store in ice (bring to ambient temperature before use).

2. 6 μM Human prothrombin (FII): dilute 124 μL of FII stock (4.85 mg/mL)to final 1400 μL with assay buffer.

3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5 M EDTA (pH 8.5) plus 19.2 mLassay buffer.

4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) plus10.56 mL of 20 mM EDTA/assay buffer.

5. Test compounds (compounds of the invention):

Prepare a working solution (5×) from 10 mM stock (DMSO) and make aseries of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

Assay Conditions and Procedure

Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 uM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 μM humanfactor II and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at room temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96-well microtiter plates.

In the first step of the assay, 10 μL of diluted test compound (5×) orbuffer was added to the plates in duplicate. Then 10 μL of prothrombin(hFII) (5×) was added to each well. Next 30 μL PTase was added to eachwell, mix for about 30 seconds. The plates were then incubated atambient temperature for 6 minutes.

In the next step, 50 μL of 20 mM EDTA (in assay buffer) was added toeach well to stop the reaction. The resulting solutions were then mixedfor about 10 seconds. Then 100 μL of 0.2 mM spectrozyme was added toeach well. The thrombin reaction rate was then measured at 405 nm for 5minutes at 10 seconds intervals in a Molecular Devices microplatereader.

Calculations

Thrombin reaction rate was expressed as mOD/min. using OD readings fromthe five minute reaction. IC₅₀ values were calculated with the log-logitcurve fit program.

The compounds of the invention demonstrated the ability to inhibitprothrombinase when tested in this assay.

EXAMPLE 11 In vivo assay

The following assay demonstrates the ability of the compounds to act asanti-coagulants.

Male rats (250-330 g) were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperformed using a Wilcoxin-matched-pairs signed rank test.

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit the clotting of the blood.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound of the following formula:

wherein: Z¹ and Z² are independently —O—, —N(R⁹)—, —S—, —S(O)—, —S(O)₂—,or —OCH₂—; R¹ and R⁴ are each independently hydrogen, halo, alkyl,nitro, —OR⁹, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or—N(H)S(O)₂R¹²; R² is —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹²,—C(NH)N(H)C(O)R⁹, —C(NH)N(H)S(O)₂R¹², or —C(NH)N(H)C(O)N(H)R⁹; R³ ishydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹,—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹¹—C(O)N(R⁹)R¹⁰,—CH(OH)C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —R¹¹—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹¹—C(O)OR⁹,—N(R⁹)C(O)R⁹, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4), —O—(C(R⁹)(R¹⁰))_(n)—R¹³(where n is 0 to 4), or —N(R¹⁴)R¹⁵; each R⁹ and R¹⁰ is independentlyhydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹¹ is a straight orbranched alkylene chain; R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic carbocyclic ring system containing from 3 to15 carbon atoms which may be partially or fully saturated or aromatic,wherein the carbon atoms may be optionally oxidized and wherein thecarbocyclic ring system is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where mis 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl,alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy,—N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; or R¹³ is a mono- , bi- ortri-cyclic heterocyclic ring system containing from 3 to 15 ring membersincluding carbon and 1 to 4 hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; R¹⁴ and R¹⁵,together with the nitrogen atom, form a mono- , bi- or tri-cyclicheterocyclic ring system containing from 3 to 15 ring members includingcarbon and 1 to 3 additional hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen, or sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is—C(O)OR⁹ or —C(O)N(R⁹)R¹⁰; provided that when R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰)_(n)—R¹³ (where n is 0), R¹³ can not be phenyl,naphthyl or piperidinyl substituted by —C(O)OR⁹; when R⁷ is—O—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0), R¹³ can not be phenyl, naphthyl,piperidinyl or pyrrolidinyl substituted by —C(O)OR⁹; and when R⁷ is—N(R¹⁴)R¹⁵, R¹⁴ and R¹⁵, together with the nitrogen atom, can not bepiperazinyl or piperidinyl substituted by —C(O)OR⁹; as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof.
 2. A pharmaceutical composition useful in treating a humanhaving a disease-state characterized by thrombotic activity, whichcomposition comprises a therapeutically effective amount of a compoundof the following formula:

wherein: Z¹ and Z² are independently —O—, —N(R⁹)—, —S—, —S(O)—, —S(O)₂—,or —OCH₂—; R¹ and R⁴ are each independently hydrogen, halo, alkyl,nitro, —OR⁹, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or—N(H)S(O)₂R¹²; R² is —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹²,—C(NH)N(H)C(O)R⁹, —C(NH)N(H)S(O)₂R¹², or —C(NH)N(H)C(O)N(H)R⁹; R³ ishydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹,—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, 13 R¹¹—C(O)N(R⁹)R¹⁰,—CH(OH)C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰; —R¹¹—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹¹—C(O)OR⁹,—N(R⁹)C(O)R⁹, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4), —O—(C(R⁹)(R¹⁰))_(n)—R¹³(where n is 0 to 4), or —N(R¹⁴)R¹⁵; each R⁹ and R¹⁰ is independentlyhydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹¹ is a straight orbranched alkylene chain; R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic carbocyclic ring system containing from 3 to15 carbon atoms which may be partially or fully saturated or aromatic,wherein the carbon atoms may be optionally oxidized and wherein thecarbocyclic ring system is substituted by —(C(R⁹)(R¹⁰)_(m)—R¹⁶ (where mis 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl,alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy,—N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; or R¹³ is a mono- , bi- ortri-cyclic heterocyclic ring system containing from 3 to 15 ring membersincluding carbon and 1 to 4 hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; R¹⁴ and R¹⁵,together with the nitrogen atom, form a mono- , bi- or tri-cyclicheterocyclic ring system containing from 3 to 15 ring members includingcarbon and 1 to 3 additional hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen, or sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is—C(O)OR⁹ or —C(O)N(R⁹)R¹⁰; provided that when R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰)_(n)—R¹³ (where n is 0), R¹³ can not be phenyl,naphthyl or piperidinyl substituted by —C(O)OR⁹; when R⁷ is—O—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0), R¹³ can not be phenyl, naphthyl,piperidinyl or pyrrolidinyl substituted by —C(O)OR⁹; and when R⁷ is—N(R¹⁴)R¹⁵, R¹⁴ and R¹⁵, together with the nitrogen atom, can not bepiperazinyl or piperidinyl substituted by —C(O)OR⁹; as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.
 3. A method oftreating a human having a disease-state characterized by thromboticactivity, which method comprises administering to a human in needthereof a therapeutically effective amount of a compound ng of thefollowing formula:

wherein: Z¹ and Z² are independently —O—, —N(R⁹)—, —S—, —S(O)—, —S(O)₂—,or —OCH₂—; R¹ and R⁴ are each independently hydrogen, halo, alkyl,nitro, —OR⁹, —C(O)OR⁹, —C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —N(R⁹)C(O)R⁹, or—N(H)S(O)₂R¹²; R² is —C(NH)NH₂, —C(NH)N(H)OR⁹, —C(NH)N(H)C(O)OR¹²,—C(NH)N(H)C(O)R⁹, —C(NH)N(H)S(O)₂R¹², or —C(NH)N(H)C(O)N(H)R⁹; R³ ishydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, —OR⁹,—C(NH)NH₂, —C(NH)N(H)OR⁹, —C(O)N(R⁹)R¹⁰, —R¹¹—C(O)N(R⁹)R¹⁰,—CH(OH)C(O)N(R⁹)R¹⁰, —N(R⁹)R¹⁰, —R¹¹—N(R⁹)R¹⁰, —C(O)OR⁹, —R¹¹—C(O)OR⁹,—N(R⁹)C(O)R⁹, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰))_(n)—R¹³ (where n is 0 to 4), —O—(C(R⁹)(R¹⁰)_(n)—R¹³(where n is 0 to 4), or —N(R¹⁴ )R¹⁵; each R⁹ and R¹⁰ is independentlyhydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹¹ is a straight orbranched alkylene chain; R¹² is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹³ isa mono- , bi- or tri-cyclic carbocyclic ring system containing from 3 to15 carbon atoms which may be partially or fully saturated or aromatic,wherein the carbon atoms may be optionally oxidized and wherein thecarbocyclic ring system is substituted by —(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where mis 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl,alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy,—N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; or R¹³ is a mono- , bi- ortri-cyclic heterocyclic ring system containing from 3 to 15 ring membersincluding carbon and 1 to 4 hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰)_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; R¹⁴ and R¹⁵,together with the nitrogen atom, form a mono- , bi- or tri-cyclicheterocyclic ring system containing from 3 to 15 ring members includingcarbon and 1 to 3 additional hetero atoms selected from nitrogen, oxygenand sulfur atoms, wherein the carbon, nitrogen, or sulfur atoms may beoptionally oxidized and wherein the heterocyclic ring system may bepartially or fully saturated or aromatic and is substituted by—(C(R⁹)(R¹⁰))_(m)—R¹⁶ (where m is 0 to 4), and is optionally substitutedby alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl,haloalkoxy, hydroxy, —N(R⁹)R¹⁰, —C(O)OR⁹, or —C(O)N(R⁹)R¹⁰; and R¹⁶ is—C(O)OR⁹ or —C(O)N(R⁹)R¹⁰; provided that when R⁷ is—N(R⁹)—(C(R⁹)(R¹⁰)_(n)—R¹³ (where n is 0), R¹³ can not be phenyl,naphthyl or piperidinyl substituted by —C(O)OR⁹; when R⁷ is—O—(C(R⁹)(R¹⁰)_(n) 13 R¹³ (where n is 0), R¹³ can not be phenyl,naphthyl, piperidinyl or pyrrolidinyl substituted by —C(O)OR⁹; and whenR⁷ is —N(R¹⁴)R¹⁵, R¹⁴ and R¹⁵, together with the nitrogen atom, can notbe piperazinyl or piperidinyl substituted by —C(O)OR⁹; as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof.